ABSTRACT AlisBio is developing novel therapeutics based on Insulin-like growth factor binding protein 2 (IGFBP2) peptide fragments to treat functional and behavioral deficits in Phelan-McDermid Syndrome (PMS), a monogenic form of autism spectrum disorder (ASD) accounting for ~2% of ASD diagnoses. The focus of this Phase I grant is to demonstrate that proprietary IGFBP2 mimetic peptide fragments reverse disease-relevant cellular, functional and behavioral deficits in a mouse model of PMS. Increasing prevalence of ASD diagnoses in the U.S. poses an enormous personal and public health challenge, with annual costs of care for children with ASD estimated to be $11-60B. Due to the immense etiological heterogeneity, development of therapeutics for ASD is extremely challenging. Drug development for etiologically-defined subtypes of ASD, such as PMS, could be achievable and could pave the way for treatment of other forms of autism. Development of the first effective pharmacological treatment for PMS would therefore have a substantial impact for the management of PMS and, potentially, ASD. There are no existing disease-modifying therapeutics for PMS or ASD on the market today. An experimental treatment based on IGFI has shown some efficacy but suffers from significant drawbacks as a long-term treatment option. The established course of treatment for PMS and ASD today leverages regular therapies (e.g. speech, physical, occupational, behavioral) to support developmental challenges and specific medications (e.g. ADHD, epilepsy, anxiety) to address the variety of specific clinical symptoms. AlisBio?s approach is valid and relies on key innovations: (1) previous research by the team showed that IGFBPs have a completely novel pharmacology producing their therapeutic effects via a unique mechanism of action, (2) the proposed research uses peptide fragments from the conserved sequences of the active IGFBPs that show high activity and potency and are well tolerated, making them ideal therapeutic agents, and (3) previous research by the team showed that IGFBP2, and therefore the proprietary peptide fragments, are superior to IGFI in its therapeutic-like effects as well as enhancing synaptic plasticity, which is the underlying deficit in PMS. The team on this STTR project has extensive published expertise on developing other peptides from preclinical testing to successful Phase II clinical trial data, as well as on investigating synaptic plasticity in neurodevelopmental disorders and ASD. The 3 Specific Aims of the proposed project are: (1) to determine the ability of proprietary IGFBP2-mimetic peptide fragments to rescue disease-relevant cellular abnormalities in Shank3-deficient mouse neurons, (2) to determine the ability of proprietary IGFBP2-mimetic peptide fragments to rescue in vivo dendritic spine morphology and in vivo auditory LTP deficits in Shank3-deficient mice, and (3) to determine the ability of proprietary IGFBP2-mimetic peptide fragments to rescue in vivo learning, memory, and vocalization quality measures in Shank3-deficient mice. Successful completion of this proposal will show that the proprietary IGFBP2 peptide fragments rescue the cellular, electrophysiological and behavioral deficits in Shank3 deficient mice. The Company will then advance the therapeutic to Phase II IND-enabling studies and follow-on clinical trials.